JAK3 is a member of Janus family which belongs to protein kinases. Other members of this family are expressed in various tissues, while JAK3 is expressed only in hematopoietic cells.
This limiting expression is involved in an important role of JAK3 by a non-covalent association of JAK3 with γ-chains common to multiply-linked receptors including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 in the receptor-mediated signal transduction.
Significantly reduced JAK3 protein levels or gene defects in common γ-chains are found in Severe Combined Immunodeficiency, referred to as SCID hereinafter, patient population. That indicates that an immunosuppression is produced by blocking JAK3-mediated signaling pathway.
It has been reported in animal experiments that JAK3 plays an important role in maturity of NK cells, B-lymphocytes and T-lymphocytes and is essentially required for the maintenance of T cell functions.
It has been also reported that a JAK3 inhibitor CP-690,550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) improves rheumatoid arthritis and psoriasis conditions, and shows rejection-suppression effects in simian renal transplantation model and airway inflammation-suppression effects in mouse asthma model.
In view of the above knowledge, it is believed that a regulation of an immune activity by JAK3 inhibitors is useful for the prevention or treatment of organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease and allergic disease.
On the other hand, it has been indicated that an inhibition of JAK2 is useful for patients suffering from a chronic myeloproliferative disease. The chronic myeloproliferative disease includes polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic myelocytic leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, chronic neutrophilic leukemia, systemic mastocytosis.
It is believed that the chronic myeloproliferative disease may be caused by acquired cell mutations in hematopoietic stem cells, and it has been reported that a large majority of polycythemia vera's patients as well as a significant number of primary myelofibrosis's and essential thrombocythemia's patients have gain-of-function mutations of JAK2. It has been also reported that an inhibition of a JAK2V617F kinase by low-molecular inhibitors causes an inhibition of proliferation of hematopoietic cells.
In view of the above knowledge, it is believed that a regulation of proliferation of hematopoietic cells by JAK2 inhibitors is useful for the prevention or treatment of chronic myeloproliferative diseases.
Four types of members of a Janus kinase, referred to as JAK hereinafter, family are known including Janus kinase 1, referred to as JAK1 hereinafter, JAK2, JAK3, and tyrosine kinase 2, referred to as Tyk2 hereinafter, and it is believed that a JAK1 inhibitor and a Tyk2 inhibitor are also useful for the prevention or treatment of varieties of diseases similar to a JAK3 inhibitor.